ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Busilvex 6 mg/ml concentrate for solution for infusion
One ml of concentrate contains 6 mg of busulfan (60 mg in 10 ml).
After dilution: 1 ml of solution contains 0.5 mg of busulfan
For a full list of excipients see section 6.1
Concentrate for solution for infusion (sterile concentrate).
Clear, colourless solution.
Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to
conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the
combination is considered the best available option.
Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning
treatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.
Busilvex administration should be supervised by a physician experienced in conditioning treatment
prior to haematopoietic progenitor cell transplantation.
Busilvex is administered prior the conventional haematopoietic progenitor cell transplantation
(HPCT).
Dosage in adults
The recommended dosage and schedule of administration is:
-
0.8 mg/kg body weight (BW) of busulfan as a two-hour infusion every 6 hours over 4
consecutive days for a total of 16 doses,
-
followed by cyclophosphamide at 60 mg/kg/day over 2 days initiated for a least 24 hours
following the 16
th
dose of Busilvex (see section 4.5).
Dosage in paediatric patients (0 to 17 years)
The recommended dose of Busilvex is as follows:
Actual body weight (kg)
Busulfex dose (mg/kg)
< 9
1.0
9 to < 16
1.2
16 to 23
1.1
> 23 to 34
0.95
> 34
0.8
2
followed by:
-
4 cycles of 50 mg/kg body weight (BW) cyclophosphamide (BuCy4) or
-
one administration of 140 mg/m² melphalan (BuMel)
initiated for a least 24 hours following the 16
th
dose of Busilvex.(see section 4.5).
Busilvex is administered as a two-hour infusion every 6 hours over 4 consecutive days for a total of 16
doses prior to cyclophosphamide or melphalan and conventional haematopoietic progenitor cell
transplantation (HPCT)
Administration
Busilvex must be diluted prior to administration (see section 6.6). A final concentration of
approximately 0.5 mg/ml busulfan should be achieved. Busilvex should be administered by
intravenous infusion via central venous catheter.
Busilvex should not be given by rapid intravenous,
bolus
or peripheral injection.
All patients should be pre-medicated with anticonvulsant medicinal products to prevent seizures
reported with the use of high dose busulfan.
It is recommended to administer anticonvulsants 12 h prior to Busilvex to 24 h after the last dose of
Busilvex.
In adults all studied patients received phenytoin. There is no experience with other anticonvulsant
agents such as benzodiazepines (see sections 4.4 and 4.5).
In children studied patients received either phenytoin or benzodiazepines.
Antiemetics should be administered prior to the first dose of Busilvex and continued on a fixed
schedule according to local practice through its administration.
Obese patients
In adults
For obese patients, dosing based on adjusted ideal body weight (AIBW) should be considered.
Ideal body weight (IBW) is calculated as follows:
IBW men (kg)=50 + 0.91x (height in cm-152);
IBW women (kg)= 45 + 0.91x (height in cm-152).
Adjusted ideal body weight (AIBW) is calculated as follows:
AIBW= IBW+0.25x ( actual body weight - IBW).
In paediatric patients
The medicinal product is not recommended in obese children and adolescents with body mass index
Weight (kg)/(m)² > 30 kg/m² until further data become available.
Renally impaired patient:
Studies in renally impaired patients have not been conducted, however, as busulfan is moderately
excreted in the urine, dose modification is not recommended in these patients.
However, caution is recommended (see sections 4.8 and 5.2).
Hepatically impaired patient
:
Busilvex as well as busulfan has not been studied in patients with hepatic impairment.
Caution is recommended, particularly in those patients with severe hepatic impairment (see section
4.4).
3
Elderly patient
:
Patients older than 50 years of age (n=23) have been successfully treated with Busilvex without dose-
adjustment.
However, for the safe use of Busilvex in patients older than 60 years only limited
information is available. Same dose (see section 5.2) for elderly as for adults (< 50 years old) should
be used.
Hypersensitivity to the active substance or to any of the excipients
Pregnancy (see section 4.6)
The consequence of treatment with Busilvex at the recommended dose and schedule is profound
myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, or
any combination thereof may develop. Frequent complete blood counts, including differential white
blood cell counts, and platelet counts should be monitored during the treatment and until recovery is
achieved.
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the
prevention and management of infections during the neutropenic period. Platelet and red blood cell
support, as well as the use of growth factors such as granulocyte colony stimulating agent (G-CSF),
should be employed as medically indicated.
In adults
, absolute neutrophil counts < 0.5x10
9
/l at a median of 4 days post transplant occurred in
100% of patients and recovered at median day 10 and 13 days following autologous and allogeneic
transplant respectively (median neutropenic period of 6 and 9 days respectively). Thrombocytopenia
(< 25x10
9
/l or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients.
Anaemia (haemoglobin< 8.0 g/dl) occurred in 69% of patients.
In paediatric patients
, absolute neutrophil counts < 0.5x10
9
/l at a median of 3 days post transplant
occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant
respectively. In children, thrombocytopenia (< 25x10
9
/l or requiring platelet transfusion) occurred in
100% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 100% of patients.
The Fanconi anaemia cells have hypersensitivity to cross-linking agents. There is limited clinical
experience of the use of busulfan as a component of a conditioning regimen prior to HSCT in children
with Fanconi’s anaemia. Therefore Busilvex should be used with caution in this type of patients.
Busilvex as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan
is mainly metabolized through the liver, caution should be observed when Busilvex is used in patients
with pre-existing impairment of liver function, especially in those with severe hepatic impairment. It is
recommended when treating these patients that serum transaminase, alkaline phosphatase, and
bilirubin should be monitored regularly 28 days following transplant for early detection of
hepatotoxicity.
Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busilvex.
Patients who have received prior radiation therapy, greater than or equal to three cycles of
chemotherapy, or prior progenitor cell transplant may be at an increased risk (see section 4.8).
Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with
Busilvex due to a possible decrease in the metabolism of busulfan (See section 4.5).
As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific
cardiac toxicities related to Busilvex. However cardiac function should be monitored regularly in
patients receiving Busilvex (see section 4.8).
4
Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with
interstitial pulmonary fibrosis was reported in Busilvex studies in one patient who died, although, no
clear aetiology was identified. In addition, busulfan might induce pulmonary toxicity that may be
additive to the effects produced by other cytotoxic agents. Therefore, attention should be paid to this
pulmonary issue in patients with prior history of mediastinal or pulmonary radiation (see section 4.8).
Periodic monitoring of renal function should be considered during therapy with Busilvex (see section
4.8).
Seizures have been reported with high dose busulfan treatment. Special caution should be exercised
when administering the recommended dose of Busilvex to patients with a history of seizures. Patients
should receive adequate anti-convulsant prophylaxis. In adults, all data with Busilvex were obtained
using phenytoin. There are no data available on the use of other anticonvulsant agents such as
benzodiazepines. Thus, the effect of anticonvulsant agents (other than phenytoin) on busulfan
pharmacokinetics is not known. (see sections 4.2 and 4.5 ).
In paediatric patients, data with Busilvex were obtained using benzodiazepines or phenytoin.
The increased risk of a second malignancy should be explained to the patient. On the basis of human
data, busulfan has been classified by the International Agency for Research on Cancer (IARC) as a
human carcinogen. The World Health Association has concluded that there is a causal relationship
between busulfan exposure and cancer. Leukaemia patients treated with busulfan developed many
different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be
leukemogenic.
Fertility: busulfan can impair fertility. Therefore, men treated with Busilvex are advised not to father a
child during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior
to treatment because of the possibility of irreversible infertility due to therapy with Busilvex. Ovarian
suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal
patients. Busulfan treatment in a pre-adolescent girl prevented the onset of puberty due to ovarian
failure. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients.
The solvent dimethylacetamide (DMA) may also impair fertility. DMA decreases fertility in male and
female rodents (see sections 4.6 and 5.3)
No specific clinical trial was carried out to assess drug-drug interaction between intravenous busulfan
and itraconazole. From published studies, in adults administration of itraconazole to patients receiving
high-dose busulfan may result in reduced busulfan clearance. Patients should be monitored for signs of
busulfan toxicity when itraconazole is used as an antifungal prophylaxis with intravenous busulfan.
Published studies in adults described that ketobemidone (analgesic) might be associated with high
levels of plasma busulfan. Therefore special care is recommended when combining these two
compounds .
In adults, for the BuCy2 regimen it has been reported that the time interval between the last oral
busulfan administration and the first cyclophosphamide administration may influence the development
of toxicities. A reduced incidence of Hepatic Veino Occlusive Disease (HVOD) and other regimen-
related toxicity have been observed in patients when the lag time between the last dose of oral
busulfan and the first dose of cyclophosphamide is > 24hours.
In paediatric patients, for the BuMel regimen it has been reported that the administration of melphalan
less than 24 hours after the last oral busulfan administration may influence the development of
toxicities.
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore
decrease busulfan clearance when used in combination (see section 4.4).
5
Phenytoin or benzodiazepines were administered for seizure prophylaxis in all patients in the clinical
trials conducted with intravenous busulfan. The concomitant systemic administration of phenytoin to
patients receiving high-dose busulfan has been reported to increase busulfan clearance, due to
induction of glutathion-S-transferase. However no evidence of this effect has been seen in intravenous
data.(see section 4.4)
No interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam
have been used to prevent seizures with high-dose busulfan (see sections 4.2 and 4.4).
No interaction was observed when busulfan was combined with fluconazole (antifungal agent) or
5 HT
3
antiemetics such as ondansetron or granisetron.
Pregnancy
HPCT is contraindicated in pregnant women ; therefore, Busilvex is contraindicated during pregnancy.
Busulfan has caused embryofoetal lethality and malformations in pre-clinical studies.(see section 5.3)
There are no adequate data from the use of either busulfan or DMA in pregnant woman. A few cases
of congenital abnormalities have been reported with low-dose oral busulfan, not necessarily
attributable to the active substance, and third trimester exposure may be associated with impaired
intrauterine growth.
Women of childbearing potential have to use effective contraception during and up to 6 months after
treatment.
Lactation
It is not known whether busulfan and DMA are excreted in human milk. Because of the potential for
tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be
discontinued at the start of therapy.
Fertility
Busulfan and DMA can impair fertility in man or woman. Therefore it is advised not to father child
during the treament and up to 6 months after treatment and to seek advice on cryo-conservation of
sperm prior to treatment because of the possibility of irreversible infertility (see section 4.4).
Not relevant
Averse events in adults
Adverse events information is derived from two clinical trials (n=103) of Busilvex.
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as
expected consequences of the conditioning regimen and transplant process. These include infection
and Graft-versus host disease (GVHD) which although not directly related, were the major causes of
morbidity and mortality, especially in allogeneic HPCT.
Blood and the lymphatic system disorders
:
Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning
regimen. Therefore all patients experienced profound cytopenia: leukopenia 96%, thrombocytopenia
94%, and anemia 88%. The median time to neutropenia was 4 days for both autologous and allogeneic
patients. The median duration of neutropenia was 6 days and 9 days for autologous and allogeneic
patients.
Immune system disorders:
6
The incidence of acute graft versus host disease (a-GVHD) data was collected in OMC-BUS-4
study(allogeneic)(n=61) . A total of 11 patients (18%) experienced a-GVHD. The incidence of a-
GVHD grades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61). Acute GVHD
was rated as serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of
death, and was reported as the cause of death in 3 patients.
Infections and infestations:
39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were
rated as mild or moderate. Pneumonia was fatal in 1% (1/103) and life-threatening in 3% of patients.
Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients and
graded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were
mild/moderate in 46% and severe in 1%.
Hepato-biliary disorders :
15% of SAEs involved liver toxicity. HVOD is a recognized potential complication of conditioning
therapy post-transplant. Six of 103 patients (6%) experienced HVOD. HVOD occurred in: 8.2% (5/61)
allogeneic patients (fatal in 2 patients) and 2.5% (1/42) of autologous patients. Elevated bilirubine
(n=3) and elevated AST (n=1) were also observed. Two of the above four patients with serious serum
hepatotoxicity were among patients with diagnosed HVOD.
Respiratory, thoracic and mediastinal disorders
:
One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratory
failure associated with interstitial pulmonary fibrosis in the Busilvex studies.
In addition the literature review reports alterations of cornea and lens of the eye with oral busulfan.
Adverse events in paediatric patients
Adverse events information are derived from the clinical study in paediatrics (n=55). Serious toxicities
involving the hepatic and respiratory systems were considered as expected consequences of the
conditioning regimen and transplant process.
Immune system disorders:
The incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients
(n=28). A total of 14 patients (50%) experienced a-GVHD. The incidence of a-GVHD grades I-II was
46.4% (13/28), while the incidence of grade III-IV was 3.6% (1/28). Chronic GVHD was reported
only if it is the cause of death: one patient died 13 months post-transplant.
Infections and infestations:
Infections (documented and non documented febrile neutropenia) were experienced in 89% of patients
(49/55). Mild/moderate fever was reported in 76% of patients.
Hepato-biliary disorders :
Grade 3 elevated transaminases were reported in 24% of patients.
Veino occlusive disease (VOD) was reported in 15% (4/27) and 7% (2/28) of the autologous and
allogenic transplant respectively. VOD observed were neither fatal nor severe and resolved in all
cases.
Adverse reactions reported both in adults and paediatric patients
as more than an isolated case are
listed below, by system organ class and by frequency. Within each frequency grouping, adverse events
are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10),
common (≥ 1/100,< 1/10), uncommon (≥ 1/1,000, < 1/100).
System organ class
Very common
Common
Uncommon
7
Infections and infestations
Rhinitis
Pharyngitis
Blood and lymphatic system
disorders
Neutropenia
Thrombocytopenia
Febrile neutropenia
Anaemia
Pancytopenia
Immune system disorders
Allergic reaction
Metabolism and nutrition
disorders
Anorexia
Hyperglycaemia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hypophosphatemia
Hyponatraemia
Psychiatric disorders
Anxiety
Depression
Insomnia
Confusion
Delirium
Nervousness
Hallucination
Agitation
Nervous system disorders
Headache
Dizziness
Seizure
Encephalopathy
Cerebral
haemorrhage
Cardiac disorders
Tachycardia
Arrhythmia
Atrial fibrillation
Cardiomegaly
Pericardial effusion
Pericarditis
Ventricular
extrasystoles
Bradycardia
Vascular disorders
Hypertension
Hypotension
Thrombosis
Vasodilatation
Femoral artery
thrombosis
Capillary leak
syndrome
Respiratory thoracic and
mediastinal disorders
Dyspnoea
Epistaxis
Cough
Hiccup
Hyperventilation
Respiratory failure
Alveolar
haemorrhages
Asthma
Atelectasis
Pleural effusion
Hypoxia
Gastrointestinal disorders
Stomatitis
Diarrhoea
Abdominal pain
Nausea
Vomiting
Dyspepsia
Ascites
Haematemesis
Ileus
Oesophagitis
Gastrointestinal
haemorrhage
Constipation
Anus discomfort
8
Hepato-biliary disorders
Hepatomegaly
Jaundice
Skin and subcutaneous tissue
disorders
Rash
Pruritis
Alopecia
Skin desquamation
Erythema
Pigmentation
disorder
Musculoskeletal and connective
tissue disorders
Myalgia
Back pain
Arthralgia
Renal and urinary disorders
Dysuria
Oligurea
Haematuria
Moderate renal
insufficiency
General disorders and
administration site conditions
Asthenia
Chills
Fever
Chest pain
Oedema
Oedema general
Pain
Pain or inflammation
at
injection site
Mucositis
Investigations
Transaminases
increased
Bilirubin increased
GGT increased
Alkaline
phosphatases
increased
Weight increased
Bun increase
Decrease ejection
fraction
Abnormal breath
sounds
Creatinine elevated
The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system,
liver, lungs, and gastrointestinal tract may also be affected.
There is no known antidote to Busilvex other than haematopoietic progenitor cell transplantation. In
the absence of haematopoietic progenitor cell transplantation, the recommended dosage of Busilvex
would constitute an overdose of busulfan. The haematologic status should be closely monitored and
vigorous supportive measures instituted as medically indicated.
There have been two reports that busulfan is dialyzable, thus dialysis should be considered in the case
of an overdose.
Since,
busulfan is metabolized through conjugation with glutathione, administration of
glutathione might be considered.
9
It must be considered that overdose of Busilvex will also increase exposure to DMA . In human the
principal toxic effects were hepatotoxicity and central nervous system (CNS) effects. CNS changes
precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case
of overdose, management would include general supportive care.
5
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Alkyl sulfonates, ATC code: L01AB01.
Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent . In aqueous media, release of
the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an
important biological mechanism for its cytotoxic effect.
Clinical trials in adults
Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the
BuCy2 regimen prior to conventional allogeneic and/or autologous HPCT derive from two clinical
trials (OMC-BUS-4 and OMC-BUS-3).
Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with
haematological disease, the majority of whom had advanced disease.
Diseases included were acute leukemia past first remission, in first or subsequent relapse, in first
remission (high risk), or induction failures; chronic melogenous leukemia in chronic or advanced
phase; primary refractory or resistant relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma, and
myelodysplastic syndrome.
Patients received doses of 0.8 mg/kg busulfan every 6 hours infusion for a total 16 doses followed by
cyclophosphamide at 60 mg/kg once per day for two days (BuCy2 regimen).
The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and
survival.
In both studies, all patients received a 16/16 dose regimen of Busilvex. No patients were discontinued
from treatment due to adverse reactions related to Busilvex.
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC)
greater than 0.5x10
9
/l was 13 days (range 9-29 days) in allogenic patients (OMC-BUS 4), and 10 days
(range 8-19 days) in autologous patients (OMC-BUS 3). All evaluable patients engrafted. There is no
primary nor secondary graft rejection. Overall mortality and non- relapse mortality at more than 100
days post-transplant was (8/61) 13% and (6/61) 10% in allotransplanted patients, respectively. During
the same period there was no death in autologous recipients.
Clinical trials in paediatric patients
Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the
BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/or autologous
HPCT derives from clinical trial F60002 IN 101 G0.
The patients received the dosing mentioned in section 4.2.
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC)
greater than 0.5x10
9
/l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15
days) in autologous patients. All children engrafted. There is no primary or secondary graft rejection.
93% of allogeneic patients showed complete chimerism. There was no regimen-related death through
the first 100-day post-transplant and up to one year post-transplant.
5.2
Pharmacokinetic properties
10
The pharmacokinetics of Busilvex has been investigated. The information presented on metabolism
and elimination is based on oral busulfan.
Pharmacokinetics in adults
Absorption
The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a 2-
hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability
of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure was observed
when comparing plasma concentrations in adult patients receiving oral and intravenous busulfan at
1 mg/kg and 0.8 mg/kg respectively. Low inter (CV=21%) and intra (CV=12%) patient variability on
busulfan exposure was demonstrated through a population pharmacokinetic analysis, performed on
102 patients.
Distribution
Terminal volume of distribution V
z
ranged between 0.62 and 0.85 l/kg.
Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these
concentrations are probably insufficient for anti-neoplastic activity.
Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin,
was about 32%.
Metabolism
Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S-
transferase mediated). The glutathione conjugate is then further metabolised in the liver by oxidation.
None of the metabolites is thought to contribute significantly to either efficacy or toxicity.
Elimination
Total clearance in plasma ranged 2.25 - 2.74 ml/minute/kg. The terminal half-life ranged from 2.8 to
3.9 hours.
Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as
unchanged busulfan. Elimination in faeces is negligible. Irreversible protein binding may explain the
incomplete recovery. Contribution of long-lasting metabolites is not excluded.
Pharmacokinetic linearity
The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfan
up to 1 mg/kg.
Pharmacokinetic/pharmacodynamic relationships
The literature on busulfan suggests a therapeutic window between 900 and 1500 µMol.minute for
AUC. During clinical trials with intravenous busulfan, 90% of patients AUCs were below the upper
AUC limit (1500 µMol.minute) and at least 80% were within the targeted therapeutic window (900-
1500 µMol.minute).
Special populations
The effects of renal dysfunction on intravenous. busulfan disposition have not been assessed.
The effects of hepatic dysfunction on intravenous busulfan disposition have not been assessed.
Nevertheless the risk of liver toxicity may be increased in this population.
No age effect on busulfan clearance was evidenced from available intravenous busulfan data in
patients over 60 years.
Pharmacokinetics in paediatric patients
A continuous variation of clearance ranging from 2.49 to 3.92 ml/minute/kg has been established in
children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h.
The dosing recommended in section 4.2. allows to achieve a similar AUC whatever the children's age,
the targeted range of AUCs being the one used for adults. Inter and intra patient variabilities in plasma
exposure were lower than 20% and 10%, respectively.
11
Pharmacokinetic/pharmacodynamic relationships:
The successful engraftment achieved in all patients during phase II trials suggests the appropriateness
of the targeted AUCs. Occurrence of VOD was not related to overexposure. PK/PD relationship was
observed between stomatitis and AUCs in autologous patients and between bilirubin increase and
AUCs in a combined autologous and allogeneic patient analysis.
5.3
Preclinical safety data
Busulfan is mutagenic and clastogenic. Busulfan was mutagenic in
Salmonella typhimurium,
Drosophila melanogaster
and barley. Busulfan induced chromosomal aberrations
in vitro
(rodent and
human cell) and
in vivo
(rodents and humans). Various chromosome aberrations have been observed in
cells from patients receiving oral busulfan.
Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism
of action. On the basis of human data, busulfan has been classified by the IARC as a human
carcinogen. WHO has concluded that there is a causal relationship between busulfan exposure and
cancer. The available data in animals support the carcinogenic potential of busulfan. Intravenous
administration of busulfan to mice significantly increased the incidences of thymic and ovarian
tumours.
Busulfan is teratogen in rats, mice and rabbits. Malformations and anomalies included significant
alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan
produced sterility in both male and female offspring due to the absence of germinal cells in testes and
ovaries. Busulfan was shown to cause sterility in rodents. Busulfan depleted oocytes of female rats,
and induced sterility in male rats and hamster.
Repeated doses of DMA produced signs of liver toxicity, the first being increases in serum clinical
enzymes followed by histopatological changes in the hepatocytes. Higher doses can produce hepatic
necrosis and liver damage can be seen following single high exposures.
DMA is teratogenic in rats. Doses of 400 mg/kg/day DMA administered during organogenesis caused
significant developmental anomalies. The malformations included serious heart and/or major vessels
anomalies: a common truncus arteriosis and no ductus arteriosis, coarctation of the pulmonary trunk
and the pulmonary arteries, intraventricular defects of the heart. Other frequent anomalies included
cleft palate, anasarca and skeletal anomalies of the vertebrae and ribs. DMA decreases fertility in male
and female rodents. A single s.c. dose of 2.2 g/kg administered on gestation day 4 terminated
pregnancy in 100% of tested hamster. In rats, a DMA daily dose of 450 mg/kg given to rats for nine
days caused inactive spermatogenesis.
6
6.1
List of excipients
Dimethylacetamide
Macrogol 400.
6.2
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products except those mentioned in section 6.6.
Do not use polycarbonate syringes with Busilvex.
6.3
Shelf life
Vials
: 2 years
12
Diluted solution
Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%)
solution for injection has been demonstrated for:
-
8 hours (including infusion time) after dilution when stored at 20 °C
±
5 °C
-
12 hours after dilution when stored at 2 °C-8 °C followed by 3 hours stored at 20 °C
±
5 °C
(including infusion time).
From a microbiological point of view, the product should be used immediately after dilution. If not
used immediately, in-use storage times and conditions prior to use are the responsibility of the user
and would normally not be longer than the above mentioned conditions when dilution has taken place
in controlled and validated aseptic conditions.
6.4
Special precautions for storage
Storein a refrigerator (2 ° C-8 °C).
Do not freeze the diluted solution.
For storage conditions of the diluted medicinal product see section 6.3
6.5
Nature and contents of container
10 ml of concentrate for solution for infusion in clear glass vials (type I) with a butyl rubber stopper
covered by a purple flip-off aluminium seal cap.
Pack size: 8 vials per box
6.6
Special precautions for disposal and other handling
Preparation of Busilvex
Procedures for proper handling and disposal of anticancer medicinal products should be considered.
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical
laminar flow safety hood
As with other cytotoxic compounds, caution should be exercised in handling and preparing the
Busilvex solution:
-
The use of gloves and protective clothing is recommended.
-
If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with
water immediately.
Calculation of the quantity of Busilvex to be diluted and of the diluent
Busilvex must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) solution for
injection or glucose solution for injection 5% .
The quantity of the diluent must be 10 times the volume of Busilvex ensuring the final concentration
of busulfan remains at approximately 0.5 mg/ml. By example:
The amount of Busilvex and diluent to be administered would be calculated as follows:
for a patient with a Y kg body weight:
•
Quantity of Busilvex:
Y (kg) x D (mg/kg)
= A ml of Busilvex to be diluted
13
6 (mg/ml)
Y: body weight of the patient in kg
D: dose of Busilvex (see section 4.2)
•
Quantity of diluent:
(A ml Busilvex) x (10) = B ml of diluent
To prepare the final solution for infusion, add (A) ml of Busilvex to (B) ml of diluent (sodium chloride
9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)
Preparation of the solution for infusion
•
Busilvex must be prepared by a healthcare professional using sterile transfer techniques.Using a
non polycarbonate syringe fitted with a needle:
-
the calculated volume of Busilvex must be removed from the vial.
-
the contents of the syringe must be dispensed into an intravenous bag (or syringe) which
already contains the calculated amount of the selected diluent. Busilvex must always be added
to the diluent, not the diluent to Busilvex. Busilvex must not be put into an intravenous bag
that does not contain sodium chloride 9 mg/ml (0.9%) solution for injection or glucose
solution for injection 5%.
•
The diluted solution must be mixed thoroughly by inverting several times
After dilution, 1 ml of solution for infusion contains 0.5 mg of busulfan
Diluted Busilvex is a clear colourless solution
Instructions for use
Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of
sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.
The residual medicinal product must not be flushed in the administration tubing as rapid infusion of
Busilvex has not been tested and is not recommended.
The entire prescribed Busilvex dose should be delivered over two hours.
Small volumes may be administered over 2 hours using electric syringes. In this case infusion sets
with minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution
prior to beginning the actual Busilvex infusion and then flushed with sodium chloride 9 mg/ml (0.9%)
solution for injection or glucose (5%) solution for injection.
Busilvex must not be infused concomitantly with another intravenous solution.
Polycarbonate syringes must not be used with Busilvex.
For single use only. Only a clear solution without any particles should be used.
Any unused product or waste material should be disposed of in accordance with local requirements for
cytotoxic medicinal products.
14
7
Pierre Fabre Médicament
45, Place Abel Gance
F-92654 Boulogne Billancourt Cedex
France
8
EU/1/03/254/002
9
Date of first authorisation: 09 July , 2003
Date of latest renewal: 08 July, 2008
15
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
16
A
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Pierre Fabre Médicament Production
Site Aquitaine Pharm International
Avenue du Béarn -Idron
F-64320
France
B
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE
AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
{Box containing 8 vials of 10ml)
1.
Busilvex 6 mg/ml concentrate for solution for infusion
busulfan
2.
STATEMENT OF ACTIVE SUBSTANCE
One ml of concentrate contains 6 mg of busulfan and provides 0.5 mg/ml of busulfan after dilution
3.
LIST OF EXCIPIENTS
Each vial contains Dimethylacetamide and Macrogol 400
4.
Concentrate for solution for infusion
Box of 8 single use vials of 10 ml
60 mg per vial
5.
METHOD AND ROUTE OF ADMINISTRATION
Intravenous use (IV)
Must be diluted before use
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING IF NECESSARY
Cytotoxic agent, special handling instructions
8.
EXPIRY DATE
EXP
20
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C)
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements
Pierre Fabre Médicament
45, place Abel Gance
F-92654 Boulogne Billancourt cedex
France
12. MARKETING AUTHORISATION NUMBERS
EU/1/03/254/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to restricted medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
21
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
{ box containing 4 vials of 10ml)
1.
Busilvex 6 mg/ml
busulfan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
60 mg
3.
LIST OF EXCIPIENTS
4.
Concentrate
10 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use (IV)
Must be diluted before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C)
Read the leaflet before use
22
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
23
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
{10ml type I glass vial}
1.
Busilvex 6 mg/ml sterile concentrate
IV
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
60 mg/10 ml
6.
OTHER
24
B. PACKAGE LEAFLET
25
PACKAGE LEAFLET:INFORMATION FOR THE USER
Busilvex 6 mg/ml concentrate for solution for infusion.
busulfan.
Read all of this leaflet carefully before you start using this medicine.
-
If you have further questions, ask your doctor or your pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist
In this leaflet
:
1.
What Busilvex is and what it is used for
2.
Before you use Busilvex
3.
How to use Busilvex
5
How to store Busilvex
6.
Further information
1.
WHAT BUSILVEX IS AND WHAT IT IS USED FOR
Busilvex contains the substance busulfan, which belongs to a group of medicines called alkylating
agents. Busilvex destroys the original bone marrow before the transplant.
Busilvex is used in adults, new-born infants, children and adolescents as a
treatment prior to
transplantation.
In adults Busilvex is used
in combination with cyclophosphamide.
In new-born infants, children and adolescents, Busilvex is used in combination with
cyclophosphamide or melphalan.
You will receive this preparative medicine before receiving a transplant of either bone marrow or
haematopoietic progenitor cell.
2.
BEFORE YOU USE BUSILVEX
Do not use Busilvex:
−
if you are allergic (hypersensitive) to busulfan or any of the other ingredients of Busilvex
−
if you are pregnant, or think you may be pregnant.
Take special care with Busilvex:
Busilvex is a potent cytotoxic medicine that results in profound decrease of blood cells. At the
recommended dose, this is the desired effect. Therefore careful monitoring will be performed.
It is possible that use of Busilvex may increase the risk of suffering another malignancy in the future.
You should tell your doctor if:
−
you have a liver, kidney, heart or lung problem
−
you have a history of seizures,
−
you are currently taking other medicines.
It may no longer be possible for you to achieve a pregnancy (infertility) after treatment with busulfan.
If you are concerned about having children, you should discuss this with your doctor before treatment.
Busilvex can also produce symptoms of menopause and in pre-adolescent girls it can prevent the onset
of puberty.
Men treated with Busilvex are advised not to father child during and up to 6 months after treatment.
26
-
Keep this leaflet. You may need to read it again.
4.
Possible side effects
Taking other medicines:
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. Busilvex may interact with other medicines.
Particular caution should be taken if you use itraconazol (used for certain types of infections) or
ketobemidone (used to treat pain), because this may increase the side-effects.
The use of paracetamol during the 72 hours prior to or with Busilvex administration should be used
with caution.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding, before you
receive treatment with Busilvex. Women must not be pregnant during treatment with Busilvex and up
to 6 months after treatment.
Women must stopbreast-feeding before starting their treatment with Busilvex.
Adequate contraceptive precautions should be used when either partner is receiving Busilvex.
3.
HOW TO USE BUSILVEX
Dosage:
In adults:
The dose will be calculated according to your body weight.
The recommended dose of Busilvex is 0.8 mg per kg of body weight, in combination with
cyclophosphamide.
In new-born infants, children and adolescents (0 to 17 years):
The recommended dose of Busilvex in combination with cyclophosphamide or melphalan is based on
your body weight varying between 0.8 and 1.2 mg/kg.
Administration:
−
Busilvex is administered by a qualified healthcare professional as a central intravenous infusion,
after dilution of the individual vial. Each infusion will last 2 hours.
−
Busilvex will be administered every 6 hours during 4 consecutive days prior to transplant.
Medicines before you receive Busilvex:
Before receiving Busilvex, you will be medicated with
−
anticonvulsive medicines to prevent seizures (phenytoin or benzodiazepines) and
−
antiemetic medicines to prevent vomiting.
27
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Busilvex can cause side effects, although not every body gets them.
Serious side effects:
The most serious side effects of Busilvex therapy or the transplant procedure may include decrease in
circulating blood cell counts (intended effect of the medicine to prepare you for your transplant
infusion), infection, liver disorders including blocking of a liver vein, graft versus host disease (the
graft attacks your body) and pulmonary complications. Your doctor will monitor your blood counts
and liver enzymes regularly to detect and manage these events.
Very common side effects (affects more than 1 user in 10):
Blood :
decrease of blood circulating cells (red and white) and platelets.
Nervous system
:
insomnia,
anxiety, dizziness, and depression.
Nutrition :
loss of appetite, decrease in magnesium, calcium,
potassium, phosphate in blood, and increase in blood sugar.
Cardiac :
increase in heart rate, increase
or decrease of blood pressure, vasodilatation (a state of increased calibre of the blood vessels), and
blood clots.
Respiratory :
shortness of breath, nasal secretion (rhinitis), sore throat, cough, hiccup,
nosebleeds, abnormal breath sounds.
Gastro-intestinal
:
nausea, inflammation of the mucosa of the
mouth, vomiting, abdominal pain , diarrhoea, constipation, heart burn, anus discomfort, liquid in the
abdomen.
Hepatic :
enlarged liver, jaundice,.
Skin
:
rash, itching, loss of hairs.
Muscle
and bone
:
back, muscle and joint pain.
Renal
:
increase in creatinine elimination, discomfort in urination, and
decrease in urine output.
General
:
, fever, headache, , weakness, chills, pain, allergic reaction,
oedema, general pain or inflammation at injection site, chest pain, inflammation of the mucosa.
Investigations
: elevated liver enzymes, weight increased
Common side effects (affects 1 to 10 users in 100 patients):
Nervous system
:
confusion.
Nutrition :
low blood sodium.
Cardiac :
changes and abnormalities in
heart rhythm, fluid retention or inflammation around the heart, decrease heart output.
Respiratory :
increase in breath rhythm, respiratory failure, alveolar haemorrhages, asthma, collapse of small
portions of the lung, fluid around the lung.
Gastro-intestinal
:
inflammation of the mucosa of
oesophagus, paralysis of the gut, vomiting blood..
Skin
: Skin colour disorder, redness of the skin, skin
desquamation
Renal
:
increase in the amount of nitrogen components in the blood stream, blood in
urines, moderate renal insufficiency.
Uncommon side effects (affects 1 to 10 users in 1,000 patients):
Nervous system
:
delirium, nervousness, hallucination, agitation, abnormal brain function, cerebral
haemorrhage, and seizure.
Cardiac :
clotting of
femoral artery, thrombosis, extra heart beats, decrease
in heart rate, diffuse leak of fluid from the capillaries (small blood vessels).
Respiratory :
decrease in
blood oxygen.
Gastro-intestinal
:
bleeding in the stomach and/or the gut.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
STORING BUSILVEX
Keep out of the reach and sight of children.
Do not use Busilvex after the expiry date which is stated on the carton.
−
Store in a refrigerator (2°C – 8°C).
−
.
Diluted solution:
Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml
(0.9%) solution for injection has been demonstrated for 8 hours (including infusion time) after dilution
28
when stored at 20 °C
±
5 °C or 12 hours after dilution when stored at 2 °C-8 °C followed by 3 hours
stored at 20 °C
±
5 °C (including infusion time).
Do not freeze
6.
FURTHER INFORMATION
What Busilvex contains
−
The active substance is busulfan. One ml of concentrate contains 6 mg busulfan (60 mg in the
vial). After dilution: one ml of solution contains approximately 0.5 mg of busulfan.
-
The other ingredients are dimethylacetamide and macrogol 400
What Busilvex looks like and contents of the pack
Busilvex consists of a concentrate for solution for infusion and is supplied in colourless glass vials,
each vial containing 60 mg of busulfan.
When diluted Busilvex is a clear colourless solution.
Busilvex is available in a box containing 8 vials.
Marketing Authorisation Holder
Pierre Fabre Médicament
45, place Abel Gance
F-92654 Boulogne-Billancourt cedex
France
Manufacturer
Pierre Fabre Médicament Production, site Aquitaine Pharm International
Avenue du béarn
F-64320 Idron
France
This leaflet was last approved on:
<------------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only
PREPARATION GUIDE
Busilvex 6 mg/ml concentrate for solution for infusion
Busulfan
Read this guide prior to the preparation and administration of Busilvex.
1.
PRESENTATION
Busilvex is supplied as a clear colourless solution in 10 ml clear glass vials (type I). Busilvex must be
diluted prior to administration.
2.
RECOMMENDATION FOR SAFE HANDLING
Procedures for proper handling and disposal of anticancer medicinal products should be considered.
29
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical
laminar flow safety hood
As with other cytotoxic compounds, caution should be exercised in handling and preparing the
Busilvex solution:
-
The use of gloves and protective clothing is recommended.
-
If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with
water immediately.
Calculation of the quantity of Busilvex to be diluted and of the diluent
Busilvex must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) solution for
injection or glucose solution for injection 5% .
The quantity of the diluent must be 10 times the volume of Busilvex ensuring the final concentration
of busulfan remains at approximately 0.5 mg/ml.
The amount of Busilvex and diluent to be administered would be calculated as follows:
for a patient with a Y kg body weight:
•
Quantity of Busilvex:
Y (kg) x D (mg/kg)
= A ml of Busilvex to be diluted
6 (mg/ml)
Y: body weight of the patient in kg
D: dose of Busilvex (see SPC section 4.2)
•
Quantity of diluent:
(A ml Busilvex) x (10) = B ml of diluent
To prepare the final solution for infusion, add (A) ml of Busilvex to (B) ml of diluent (sodium chloride
9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)
Preparation of the solution for infusion
Busilvex must be prepared by a healthcare professional using sterile transfer techniques.
•
Using a non polycarbonate syringe fitted with a needle:
-
the calculated volume of Busilvex must be removed from the vial.
-
the contents of the syringe must be dispensed into an intravenous bag (or syringe) which
already contains the calculated amount of the selected diluent. Busilvex must always be added
to the diluent, not the diluent to Busilvex. Busilvex must not be put into an intravenous bag
that does not contain sodium chloride 9 mg/ml (0.9%) solution for injection or glucose
solution for injection 5%.
•
The diluted solution must be mixed thoroughly by inverting several times
After dilution, 1 ml of solution for infusion contains 0.5 mg of busulfan
Diluted Busilvex is a clear colourless solution
Instructions for use
Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of
sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.
30
The residual medicinal product must be flushed in the administration tubing as rapid infusion of
Busilvex has not been tested and is not recommended.
The entire prescribed Busilvex dose should be delivered over two hours.
Small volumes may be administered over 2 hours using electric syringes. In that case infusion sets
with minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution
prior to beginning the actual Busilvex infusion and then flushed with sodium chloride 9 mg/ml (0.9%)
solution for injection or glucose (5%) solution for injection.
Busilvex must not be infused concomitantly with another intravenous solution.
Polycarbonate syringes must not be used with Busilvex.
For single use only. Only a clear solution without particles should be used.
3.
PROCEDURE FOR PROPER DISPOSAL
Any unused product or waste should be disposed of in accordance with local requirements for
cytotoxic medicinal products.
31
Source: European Medicines Agency
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